Targeting obesity-related adipose tissue dysfunction to prevent cancer development and progression

Author's Accepted Manuscript

Targeting Obesity-Related Adipose Tissue Dysfunction to Prevent Cancer Development and Progression Ayca Gucalp M.D., Neil M. Iyengar M.D., Clifford A. Hudis M.D., Andrew J. Dannenberg M.D.

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S0093-7754(15)00177-3 http://dx.doi.org/10.1053/j.seminoncol.2015.09.012 YSONC51868

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Cite this article as: Ayca Gucalp M.D., Neil M. Iyengar M.D., Clifford A. Hudis M.D., Andrew J. Dannenberg M.D., Targeting Obesity-Related Adipose Tissue Dysfunction to Prevent Cancer Development and Progression, Semin Oncol, http://dx.doi.org/ 10.1053/j.seminoncol.2015.09.012 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Title: Targeting obesity-related adipose tissue dysfunction to prevent cancer development and progression Authors: Ayca Gucalp, Neil M. Iyengar, Clifford A. Hudis, Andrew J. Dannenberg Ayca Gucalp M.D. Assistant Attending, Breast Medicine Service Department of Medicine Memorial Sloan Kettering Cancer Center Instructor of Medicine Weill Cornell Medical College Neil M. Iyengar M.D. Assistant Attending, Breast Medicine Service Department of Medicine Memorial Sloan Kettering Cancer Center Instructor of Medicine Weill Cornell Medical College Associate Attending Physician Rockefeller University Clifford A. Hudis M.D. Chief, Breast Medicine Service Attending, Department of Medicine Memorial Sloan Kettering Cancer Center Professor of Medicine Weill Cornell Medical College Andrew J. Dannenberg M.D. Professor of Medicine Weill Cornell Medical College Grant Support: This work was supported by grants NIH/NCI R01CA154481, the Botwinick-Wolfensohn Foundation (in memory of Mr. and Mrs. Benjamin Botwinick), and the Breast Cancer Research Foundation. Corresponding Author Info: Ayca Gucalp, Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, New York, NY 10065. Phone: 646-888-4536; Fax: 646-888-4917. E-mail: [email protected]. Conflict of Interest: None

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Abstract The incidence of obesity, a leading modifiable risk factor for common solid tumors, is increasing. Effective interventions are needed to minimize the public health implications of obesity. Although the mechanisms linking increased adiposity to malignancy are incompletely understood, growing evidence points to complex interactions among multiple systemic and tissue-specific pathways including inflamed white adipose tissue. The metabolic and inflammatory consequences of white adipose tissue dysfunction collectively provide a plausible explanation for the link between overweight/obesity and carcinogenesis. Gaining a better understanding of these underlying molecular pathways and developing risk assessment tools that identify at-risk populations will be critical in implementing effective and novel cancer prevention and management strategies.

I.

Introduction:

Obesity rates continue to rise in the US and in most other industrialized nations. Greater than one third of the US population is obese, defined as a body mass index (BMI) of ≥ 30 kg/m2.1 If the current trends continue, it is estimated that by the year 2030 >50% of the population of 39 states will be obese.2 Epidemiologic studies link obesity with an increased risk of epithelial malignancies.3,4 In 2007, more than 50,000 new cases of cancer in women (7%) and 34,000 new cases in men (4%) were attributable to obesity.5 Accordingly, obesity is projected to

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replace tobacco as the most common modifiable risk factor for the development of some of the leading preventable causes of death in the US including cardiovascular disease, stroke, and malignancy. In addition to cancer risk, obesity is also associated with poorer cancer-specific outcomes, including higher risk of cancer recurrence and mortality.6-8 Although the mechanisms linking increased adiposity to malignancy remain incompletely understood, growing evidence suggests that complex interactions between multiple pathways regulating steroid hormone synthesis, insulin resistance, adipokine and cytokine production, and chronic local and systemic inflammation may collectively explain the link between overweight/obesity and carcinogenesis.

Adipose tissue is increasingly recognized as an active endocrine organ that secretes several adipose tissue-specific hormones, including adipokines. Adipose tissue plays a significant role in the regulation of energy balance and homeostasis.9 Obesity, which is most commonly defined by BMI, is associated with increased adipocyte number, adipocyte hypertrophy, and metabolic dysfunction. Specifically, the metabolic disturbances associated with obesity include changes in steroid hormone and adipokine production, insulin resistance, dyslipidemia, and subclinical chronic inflammation.10,11 Among many other health consequences, these metabolic alterations involve pathways known to contribute to cancer development, progression, and metastasis.11 In addition to

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being common in the setting of obesity, adipose tissue dysfunction and its consequences including insulin resistance, dyslipidemia and white adipose tissue (WAT) inflammation have also been reported in individuals with normal BMIs.12,13 White adipose tissue is one of two types of fat found in mammals, the other being brown adipose tissue. In contrast to brown adipose tissue which generates heat, WAT stores fat and acts as a thermal insulator, to maintain body temperature. Of course, not all obese individuals develop obesity-related metabolic or cardiovascular disorders and some appear to have preserved normal adipose tissue function.14-16 These metabolically healthy obese individuals are, however, in the minority. Together, these observations highlight the limitations of BMI as a measure of adipose tissue function. Intra-abdominal or visceral adipocytes have the highest rates of metabolic activity17 and truncal obesity has been associated with greater incidence of metabolic derangements.18 The key issue is that BMI alone is not an adequate surrogate of adipose tissue function. Therefore, a clearer understanding of the underlying biology linking obesity and carcinogenesis will be critical for the identification of high-risk individuals and for the development of mechanism-based interventions for the safe and effective prevention and treatment of cancer. It is clear that effective and broadly applicable interventions are needed to decrease the societal impact of this shift in disease causation. Thus, the development of minimally-invasive risk assessment tools represents a critical unmet need. The specific goal is to identify the

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targetable underlying pathophysiology often but not exclusively associated with obesity. Therefore, this review focuses on the underlying biologic mechanisms associated with impaired adipose tissue function in the context of cancer development. In addition, we will examine potential interventions and strategies to reduce the unfavorable impact of obesity on cancer pathogenesis and progression.

II.

Adipose tissue dysfunction and metabolism

WAT plays a key role in the regulation of energy balance, which is mediated by the production and secretion of metabolically active proteins. Several lines of evidence suggest that obesity-induced tumor development, invasion, and progression are mediated by a complex interplay of systemic alterations at the center of which is dysfunctional adipose tissue.11 In this section, we will review these potentially carcinogenic derangements in WAT including changes in levels of several hormones, adipokines, and proinflammatory mediators.

Insulin resistance, lipid metabolism and the metabolic syndrome Obesity is associated with insulin resistance, characterized by elevated circulating levels of insulin and glucose. Epidemiologic evidence suggests that individuals diagnosed with non-insulin-dependent diabetes mellitus (NIDDM) are at significantly higher risk for several cancers notably breast, endometrial,

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colorectal, pancreatic, urinary tract, and hepatocellular cancer.19,20 Furthermore, a history of NIDDM has been associated with worse long-term survival outcomes in patients with breast and several other cancers.21-23 There are several possible common mechanisms supporting a biological link between diabetes and cancer.

Insulin has been suggested to stimulate carcinogenesis by inducing the synthesis of insulin-like growth factor-1 (IGF-1) and activating insulin/IGF-1 receptors that can be overexpressed in human cancer cells.21 Downstream activation of the RasRaf-MAPK and PI3K/Akt pathways ultimately leads to increased tumor cell proliferation, and inhibition of apoptosis.20,24,25 Furthermore, IGF-1 and insulin interact with hormone signaling pathways and may impact the growth and progression of hormonally-driven cancers. Moreover, increased insulin levels can lead to decreased hepatic production of steroid hormone binding globulin (SHBG) that normally binds to circulating steroid hormones.4 A decrease in SHBG levels resulting in increased circulating free estradiol and androgens may also contribute to tumorigenesis and progression of hormone-dependent tumors.

In addition, insulin has critical effects on lipid metabolism. Under normal physiologic conditions, insulin promotes lipid synthesis and inhibits the degradation of lipids. In contrast, obesity-related insulin resistance is associated with increased lipolysis resulting in the release of free fatty acids (FFA).26,27

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Increased levels of FFA in the circulation can lead to ectopic fat deposition in organs such as the liver, pancreas, skeletal muscle, and heart leading to disruption of metabolic processes, impairment of organ function, and further promotion of insulin resistance, hyperglycemia, dyslipidemia, and hypertension.28 Along with central obesity, these conditions are components of the metabolic syndrome.29 The metabolic syndrome has been associated with development of NIDDM, cardiovascular disease, and more recently several cancers including breast, endometrial, colon, pancreatic, liver, and bladder cancer.30-33 Altered adipokine production Adipokines, which are bioactive proteins synthesized and secreted from adipose tissue, play an important role in lipid metabolism, insulin sensitivity, inflammation,

regulation

of

energy

balance,

angiogenesis,

and

cell

proliferation.11,34 Cross-talk between leptin and adiponectin-induced signaling pathways are thought to maintain metabolic homeostasis and balance cell proliferation and apoptosis. Obesity is commonly associated with altered levels of adipokines particularly increased leptin and decreased adiponectin levels in the circulation.34 Furthermore, adipokine deregulation is implicated in cancer progression and metastasis.35

Adiponectin. Several preclinical and epidemiologic studies suggest an inverse relationship between adiponectin levels and risk for the development and

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progression of multiple cancers. Adiponectin can inhibit cell proliferation, induce apoptosis, and decrease invasion in cellular models of multiple cancers.36-39 Furthermore, preclinical work in mouse models has shown that lower levels of adiponectin results in accelerated hepatic tumor growth40 and increased colon polyp formation.41 Observational studies suggest a correlation between higher levels of adiponectin and decreased risk of postmenopausal breast cancer, uterine cancer and colorectal cancer.42-46 Variants of the adiponectin (ADIPOQ) and adiponectin receptor 1(ADIPOR1) genes have been associated with increased breast, colorectal and prostate cancer risk.47-49 Adiponectin is thought to affect cell cycle regulation, proliferation and apoptosis through the activation of multiple signaling pathways downstream of the adiponectin receptors, AdipoR1 and AdipoR2, including adenosine monophosphate-activated protein kinase (AMPK), PI3K/mTOR and the transcription factor, nuclear factor-kappaB (NFκB).50-52

Leptin. Leptin is primarily produced in the adipocyte and plays a key role in regulating energy intake and expenditure both centrally, by acting on receptors in the hypothalamus, and peripherally through modulation of glucose and insulin metabolism.53 Obese individuals generally have higher circulating levels of leptin in comparison to individuals with normal BMI.34 Similar to adiponectin, leptin and its transmembrane receptor (ObR) have been implicated in tumor

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development and metastasis.52,54-57 Leptin is known to activate the JAK/STAT, MAPK/ERK and PI3K/Akt signaling pathways leading to increased cell migration, invasion and cell survival. Additionally, leptin promotes cell proliferation via alteration of cell cycle checkpoints and up-regulation of the cdk2 and cyclin D1 genes, advancing cells from G1 to S phase.50 Finally, leptin has also been reported to have both proinflammatory and angiogenic properties, which may play a role in carcinogenesis (Figure 1). Cancer cell lines exposed to leptin demonstrate increased proliferation, migration, and invasion. In both in vitro and in vivo models of breast cancer, leptin receptor deficiency has been associated with growth suppression and decreased tumor volume. Epidemiologic data regarding leptin and cancer risk remain mixed, however. Several studies have reported a direct association between elevated circulating levels of leptin and increased risk of breast, endometrial, colorectal and prostate cancer, while others have demonstrated no association or an inverse correlation.11,58 Furthermore, increased expression of the leptin receptor has been correlated with decreased survival in ovarian cancer59 and the development of distant metastases in breast cancer.60

More recently, the leptin to adiponectin ratio has been described as a potential marker of cancer risk and outcomes as adiponectin has been shown to counteract the effects of leptin on cellular behavior. In prostate cancer cell lines, leptin can

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overcome the anti-proliferative effects of adiponectin61 and in in vitro models of hepatocellular carcinoma, adiponectin can block leptin-induced cell proliferation.62 Population-based observational studies have demonstrated a positive correlation between this ratio and increased risk of endometrial, prostate, and breast cancer.63-65 In addition to risk, a direct association between increased leptin to adiponectin ratio and tumor aggressiveness and size has been reported in breast cancer.66 These findings suggest that the balance between these two adipokines may play a central role in risk assessment in the setting of obesityinduced carcinogenesis.

Steroid hormone synthesis Estrogen. Somewhat paradoxically, epidemiologic data demonstrate an increased incidence of hormonally-driven cancers among postmenopausal women. Increasing BMI is one known risk factor for the development of postmenopausal hormone receptor-positive breast cancer as it is for endometrial cancer.67,68 The effect of overweight and obesity on cancer risk in premenopausal women is less clearly defined. While obesity among premenopausal women has been associated with an increased risk of colorectal cancer and possibly malignant melanoma,68 it has been reported in some, but not all studies to have an inverse association in terms of breast cancer risk. Among premenopausal women, estrogen is produced primarily in the ovaries. The transition into menopause is associated with a

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decline of ovarian function, decreased estrogen production, and a relative shift in estrogen production to extragonadal sites such as adipose tissue. Peripheral conversion of androgens to estrogens is catalyzed by the enzyme aromatase, encoded by the CYP19 gene. Notably, the incidence of hormone receptor-positive breast cancer increases with age in spite of the decrease in circulating estrogen levels with menopause.69 Weight gain and central adiposity associated with menopause are thought to contribute to this seemingly paradoxical phenomenon as circulating estrogen levels are higher among overweight and obese versus normal weight postmenopausal women.70

Hormone receptor-positive breast cancer development and growth are believed to be dependent on locally produced estrogens, and, possibly, ligand-independent activation of estrogen receptor-α.71 Estrogens can directly stimulate cell division and proliferation, inhibit apoptosis, and induce angiogenesis.42,43 Multiple interactive signaling pathways involving estrogen and its receptors, insulin and IGF-1, and adipokines are also implicated in breast carcinogenesis. Furthermore, complex interactions between adipocytes and immune cells, such as macrophages, have been shown to result in local WAT inflammation (WATi) which appears to be associated with enhanced local estrogen receptor-alpha signaling.

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Androgens.

The relationships among obesity, androgens, and tumorigenesis

represent an area of active investigation. While epidemiologic studies regarding obesity and risk of prostate cancer development have yielded mixed results, obesity has consistently been associated with poorer outcomes and higher grade disease.72-74 The underlying mechanisms for these observations remain incompletely understood. Inflammatory cytokines, e.g., IL-6, and IGF-1 have been implicated in the modulation of androgen receptor (AR) signaling in prostate cancer cell lines.75 Furthermore, in obese men, circulating levels of total testosterone are decreased76 suggesting potential ligand independent AR activation by cytokines or growth factors as a mechanism underlying the link between obesity and the development of high grade prostate cancer. Furthermore, obesity-induced WATi is associated with increased levels of proinflammatory mediators which may contribute to tumor formation and progression via either local or systemic interactions with the AR-signaling pathway.

Local and systemic inflammation Emerging data point to chronic inflammation as a potentially targetable risk factor for the development and progression of multiple malignancies.4,77,78 Obesity has been identified as a cause of both local and systemic inflammation. In this section, we will explore the complex local and systemic effects of obesity-induced

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inflammation and how these processes promote malignant transformation and tumor progression.

The tumor microenvironment is comprised of stromal components including fibroblasts, blood and lymphatic vessels, and immune cells, e.g., macrophages and lymphocytes. Adipocytes are also present in the microenvironment of some tumor types. Similar to a wound, the microenvironment surrounding tumor cells is characterized by aggregation of immune cells and production of inflammatory cytokines.79 Infiltration of non-tumorous WAT by macrophages and lymphocytes has also been reported among obese individuals26 and may provide a proneoplastic microenvironment.80

As discussed earlier, WATi is well described as a driver of several obesityassociated diseases including NIDDM, dyslipidemia, and cardiovascular disease.26 Recently, there has been increased focus on the complex interactions between adipocytes and the immune cell component of the stromal-vascular fraction. Macrophages comprise up to 40% of the cells in obese WAT and produce several proinflammatory cytokines that contribute to obesity-related insulin resistance.81 Emerging data suggest a central role for the macrophageadipocyte interaction in connecting WATi and cancer promotion.

13

Increased BMI is associated with adipocyte hypertrophy and death. Adipocyte death is associated with increased production of chemokines and recruitment of macrophages.82 Infiltrating macrophages surround the dead or dying adipocyte and form a crown-like structure (CLS).83 This histologic structure was first described in the setting of metabolic disorders, such as diabetes, and more recently has been identified in both the mammary gland of obese mice and in human breast tissue (termed CLS-B).83,84 The presence of these inflammatory foci is associated with activation of NF-κB and increased levels of proinflammatory mediators including tumor necrosis factor α (TNFα), interleukin 1β (IL-1β), interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) (Figure 1). Importantly, increased circulating levels of proinflammatory mediators are commonly found in obese women and have been associated with breast cancer development and progression.85-87 Furthermore, gene expression profiling of breast tissue from obese women has demonstrated an excess of monocyte and macrophage-associated genes.88

The presence of CLS and the associated increase in tissue levels of proinflammatory mediators, are believed to stimulate transcription of CYP19 leading to increased expression of aromatase, the rate-limiting enzyme responsible for estrogen synthesis.89 This finding is consistent with prior evidence that proinflammatory mediators associated with WATi, including TNF-

14

α, COX-2, and IL-1β can induce aromatase.89-91 Through these pathways, WATi is believed to be associated with increased local production of estrogen thereby linking obesity with the development of hormone-sensitive breast cancers. Additionally, the postmenopausal state was recently shown to be associated with WATi, independently of BMI, which further supports the role of adipose inflammation in the development of postmenopausal hormone-sensitive breast cancers.92 Adipose inflammation may also be associated with ligand-independent activation of ER-signaling.

Collectively, these findings provide evidence that WATi, manifest as CLS-B, is likely to be a driver of estrogen-signaling in the breast. This highlights a potential role of WATi in breast cancer pathogenesis and may partially explain the seemingly paradoxical phenomenon of the increased incidence of estrogensensitive breast cancer after menopause.93,94

While both the presence and severity of WATi are associated with increased BMI,82,84,95 WATi also occurs in a minority of women (and men) with normal BMI.92 Furthermore, aromatase activity correlates more strongly with the severity of WATi than with BMI.84 These findings underscore the central role of inflammation, rather than obesity alone, as a driver of aromatase activity in the breast and highlight CLS as a potential actionable target in this setting. In

15

addition, the observation that WATi is present in some normal BMI individuals and is absent in a minority of obese individuals, is consistent with reports of obese individuals, albeit a minority, who are metabolically healthy.14-16 This point emphasizes the clinical significance of developing biomarkers of adipose inflammation that accurately select for at-risk individuals as we strive to develop effective prevention and management strategies.

Taken together, these findings support the existence of an obesity-inflammationaromatase axis active in the breasts of a majority of overweight and obese women and a smaller subset of normal weight women. However, the proinflammatory mediators that are enriched in inflamed WAT may also drive the development and progression of other subtypes of breast cancer and other tumor types. Reversing chronic inflammation associated with adipose tissue dysfunction may become a clearer goal as we gain a more comprehensive understanding of the complex signaling pathways underlying this process.

III.

Diagnostic and interventional strategies

Key to the development of effective risk reduction and therapeutic strategies will be the ability to accurately identify at-risk populations who harbor the detrimental biology discussed in the preceding section. Potential intervention strategies in this setting can be broadly grouped into the following categories: 1) preventing or

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reversing increased adiposity; 2) targeting metabolic alterations associated with adipose tissue dysfunction; and 3) targeting white adipose tissue inflammation. A key challenge is identifying subsets of the population that can be both selected and possibly tracked to determine if a putative intervention is actually beneficial. Reliable surrogates that serve as early indicators of both risk and effective risk reduction are needed. Until we have such surrogates, we are forced to rely on broader population-based approaches.

Weight reduction is one potential strategy to suppress inflammation and consequently reduce cancer risk and improve prognosis. Weight loss achieved with a very low calorie diet has been shown to significantly improve the inflammatory gene expression profiles of obese subjects.96 Weight loss or maintenance of a normal BMI, achieved by dietary modification and/or physical activity, has been associated with improved outcomes after breast cancer diagnosis.97-105 Women randomized to the low fat diet group in the Women’s Intervention Nutrition Study lost an average of 2.77 kg and had a 24% reduction in the risk of breast cancer relapse.105 Preclinical studies have also demonstrated that calorie restriction halts weight gain in a mouse model of diet-induced obesity and is associated with a reduction in mammary gland inflammation, normalization of levels of proinflammatory mediators, and aromatase.106 Furthermore, several studies demonstrate significant associations between weight loss and

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improvements in circulating levels of insulin, estrogens, and proinflammatory mediators.99,107-110 Bariatric surgery can result in significant and sustained weight loss and is associated with post-operative decreases in adipose tissue macrophage density, reduced tissue levels of chemokines involved in immune cell recruitment, and decreased cancer incidence and improved outcomes among female patients when compared to matched controls.111-113 Collectively, these findings suggest the potential utility of improved energy balance by limiting caloric intake as a strategy to reverse obesity-associated inflammation and potentially reduce cancer development or related mortality. However, achieving and maintaining an improved state of energy balance remains difficult and, as mentioned above, some normal BMI individuals harbor WATi, calling into question our ability to fully exploit caloric restriction as a general strategy to address inflammation. Several common medications have been investigated for their potential cancer chemopreventive properties that could be relevant in the context of obesity and inflammation.114-117 Notably, metformin, statins, nonsteroidal anti-inflammatory drugs (NSAIDs) and docosahexaenoic acid (DHA) have been extensively studied in several tumor types. Although retrospective observational studies have described reduced cancer incidence associated with several of these agents and preclinical studies highlight potential antineoplastic mechanisms, in general these agents have not consistently demonstrated anticancer effects in prospective studies. Numerous studies of metformin are ongoing (see Heckman-Stoddard et

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al. in this volume). Docosahexaenoic acid (DHA), an omega-3 fatty acid, is thought to suppress inflammation by multiple mechanisms including inhibiting TLR4-activated signaling pathways that induce TNF-α and COX-2. Fatty fish and organ meats are the main sources of DHA, with smaller amounts coming from shellfish, eggs, and poultry. Diets high in fish oil have been associated with a reduced risk of breast cancer 118-121 and similar diets protect against experimental models of breast cancer.122,123 A multicenter, randomized, placebocontrolled phase II study in women with a history of premalignant breast lesions or invasive breast cancer, which is being conducted through the NCI/DCP MD Anderson Early Phase Chemoprevention Consortium, was designed to evaluate the anti-inflammatory effects of DHA on tissue level proinflammatory markers. This trial is currently open and enrolling patients (NCT01849250).124 The conflicting results reported in epidemiologic studies may be explained, in part by overtreatment resulting from the limitations associated with current risk stratification models. That is, until we can select the at-risk subset, we will be distributing an intervention across a broad population of potentially sensitive and insensitive patients, thereby diluting any potential favorable effect. This is why a key initiative must be the identification of high-risk populations to optimize the potential beneficial effects of these agents.93

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IV.

Future Directions

It is clear that BMI alone is not an adequate surrogate of WAT health. As we have learned more about WATi, it has become clear that its associated metabolic aberrations are likely to go clinically unrecognized in large numbers of patients including a subset of individuals with normal BMI. A promising strategy to improve our current risk assessment abilities, would be the development of bloodbased biomarkers that can accurately identify dysfunctional and/or inflamed WAT. Such an approach could eliminate the need for serial invasive sampling of WAT to assess the impact of interventions and could identify individuals likely to benefit from mechanistically-based risk reduction and treatment strategies. Studies involving the collection of paired serum/plasma and WAT samples are ongoing, with the goal of developing a predictive model to accurately discriminate the presence or absence of WATi. The development of a predictive signature of WATi to aid in both patient selection and monitor response to treatment should be important in improving cancer prevention and post-diagnosis outcomes for the large and growing number of patients with adipose tissue dysfunction.

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Figure 1

Local and systemic mechanisms underlying obesity and cancer promotion. Reprinted with permission.125

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